1. Field of the Invention
The present invention relates to novel phenylacetate derivatives or pharmaceutically acceptable salts thereof, a preparation method thereof, and a composition for prevention or treatment of diseases induced by activation of a T-type calcium ion channel containing the same as an active ingredient.
2. Description of the Related Art
These calcium ion channels are divided into a high-voltage activated calcium channel and a low-voltage activated calcium channel, among which a T-type calcium ion channel is a representative low-voltage activated calcium channel.
Calcium ion channels play an important role in the intracellular signal transduction by increasing intracellular calcium concentration through nerve cell stimulation. These calcium channels are divided into a high-voltage activated calcium channel and a low-voltage activated calcium channel, and a T-type calcium ion channel is a representative example of the low-voltage activated calcium channels. The T-type calcium ion channel is found in central muscles, endocrine glands in the adrenal, sinoatrial node, and heart. A T-type calcium ion channel antagonist is known to have therapeutic effect on brain diseases, such as epilepsy and hypertension cardiac diseases, such as encephalopathy and angina pectoris [Hosravani, Houman et al., “Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy”, Annals of Neurology (2005), 57(5), 745-749; Vitko, Iuliia et al., “Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel”, Journal of Neuroscience (2005), 25(19), 4844-4855]. A recent study reported that a T-type calcium ion channel antagonist has an activity in treatment of chronic pain [Drugs of the Future (2005), 40, 573-580]. For example, Mibefradil and Ethosuximide, as T-type calcium ion channel antagonists, showed dosage-dependent reversed mechanic and thermal induction in a spinal nerve ligation animal model, thus ascertaining that the T-type calcium ion channel antagonists have a therapeutic effect on neurogenic pains [Barton, Matthew E. et al., “The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil”, European Journal of Pharmacology (2005), 521(1-3), 79-85].
Calcium plays an important role as an intracellular messenger and regulates a variety of cellular processes. Calcium is known to be involved in cell growth among the cellular processes, and it is expected that a T-type calcium ion channel antagonist may have an anticancer activity [Nat. Rev. Mol. Cell Biol. 2003, 4, 517-529].
Calcium channel blockers can be classified into three classes: dihydropyridines (e.g., nifedipine), benzothiazepines (e.g., diltiazem), and phenylalkylamines (e.g., verapamil).
When the current is measured, a T-type calcium ion channel is activated at potential near the resting membrane potential, and the current is quickly activated and referred to as “transient” due to its fast inactivation. As the single channel conductance in the calcium ion channel has tiny characteristics compared to different calcium ion channels, the calcium ion channel is referred to as “T-type calcium ion channel” after the first alphabet representing these characteristics. Compared to other calcium ion channels, the T-type calcium ion channel has the activation of such a low threshold that it serves as a pacemaker, which produces simultaneous action potentials in the sinoatrial node and nerve cells, leading to the atrium contraction and is known to be involved in smooth muscle contraction, secretion of cortisol and aldosterone in adrenal cortex, excitability of Nerve, and development of tissues. In the T-type, 3 classes of the subtype cDNA are cloned and expressed. Each of them is expressed as a1G (Cav3.1), a1H (Cav3.2), and a1I (Cav3.3), and then the measured currents exhibit characteristics such as activation and inactivation reaction rates, slow activation reduction, and tiny single channel conductance as known in the art. However, the a1I shows very slow activation and inactivation reaction rates compared to the a1G and a1H.
Much has not yet been known about the T-type due to the lack of the specific blockers, and more researches should be carried out. Recent studies show that in addition to functions by the calcium ion channels, such as muscular contraction, synaptic transmission, hormone secretion, control of enzyme activity, and control of gene expression, knockout of genes encoding calcium ion channels and a variety of hereditary diseases related to nerve, muscle, and visual sense are induced by mutation in the calcium ion channel. Thus, the importance of studies on calcium ion channels is being emphasized. Most of the calcium ion channel antagonists used in the studies as drugs have shown a physiological activity predominantly in the L-type calcium ion channels. However, these drugs show side effects such as excessive contraction of muscles, increased secretion from neurohormones, and coronary occlusion. Therefore, to reduce these side effects and enhance the efficacy of the drugs, screening efforts to find blockers which exhibit a selective activity to the T-type are underway.
Among the conventional calcium ion channel blockers, flunarizine, U-92032, nicardipine, and mibefradil are exemplary materials which show a selective inhibitory activity. These usually have diphenylmethylpiperazine or dihydropyridine structures as a basic framework.
Mibefradil is the first commercially available as a T-type calcium ion channel antagonist. The mibefradil showed more inhibitory activity to the T-type than to the L-type by 10 to 30 times, but was banned from the market due to drug interactions with antihistamines such as especially, astemizole to be metabolized in cytochrome P-450 3A4 and 2D6. Therefore, there remains a demand on urgent development of T-type calcium ion channels.
There have been many efforts to develop T-type calcium ion channel antagonists, but there are few selective T-type calcium ion channel antagonists. Compounds with quinazoline as a basic framework are disclosed in Korean Pat. Nos. 784,195, 754,325, and 749,743. Compounds with isoxazole as a framework are disclosed in Korean Pat. No. 616,099, and compounds with 1,3-dioxoisoindole as a framework are disclosed in Korean Pat. No. 743,255.
However, there still remains a demand on T-type calcium ion channel antagonists with good selectivity to T-type calcium ion channels, good pharmacokinetics profile, good ADME (adsorption, distribution, metabolism, excretion) and having a therapeutic effect on related diseases such as hypertension, cancer, epilepsy, and neurogenic pains. Thus, there is a need to develop materials which have a different structure from conventional T-type calcium ion channel antagonists and a higher selectivity.
The present inventors attempted to develop novel T-type calcium ion channel antagonists which may effectively inhibit the activity of T-type calcium ion channels, synthesized novel phenylacetate derivatives, and confirmed that the phenylacetate derivatives show the inhibitory activity of T-type calcium ion channels, thereby leading to completion of the present invention.